Variations in BRCA2 and CHEK2 genes can increase lung cancer risk, study finds

Genetic causes of lung cancer explored in global genome project

New research confirms a vulnerability to lung cancer can be inherited and implicates the BRCA2 gene as harboring one of the involved genetic mutations. An international consortium of scientists including investigators at the Institute for Cancer Research in London, the International Agency for Research on Cancer in Lyon, the National Cancer Institute in Bethesda, Harvard, and Dartmouth used integrated results from the 1000 Genomes Project with genetics studies of lung cancer to complete the investigation published on June 1, 2014 in Nature Genetics.

The study scanned the genomes of more than 11 thousand individuals of European descent to look for common variations associated with non-small cell carcinoma, a common form of lung cancer. The analysis showed that variations in the BRCA2 and CHEK2 genes can significantly increase an individual's risk for lung cancer. A smoker's chances of developing lung cancer may be doubled if he or she carries the BRCA2 variation. In addition, the TP63 gene, which previously was only associated with lung cancer risk in Asian populations, was associated with risk for adenocarcinoma, a form of non-small cell carcinoma, in those of European descent.

The study used four genome-wide association (GWA) studies from the U.T. M.D. Anderson Cancer Center, the Institute of Cancer Research, the National Cancer Institute, and the International Agency for Research on Cancer. Scientists used imputation, a statistical form of inference, in which data from a reference set of individuals who have been sequenced is used to fill in missing values on the genome for the study participants. The study validated the use of this approach in finding common genetic variations between multiple sets of data and by extensively genotyping additional participants from Harvard, the International Agency for Research in Cancer, the University of Toronto, the Institute of Cancer Research, and the German Cancer Research Institute.

Chris Amos, PhD, senior author of the paper and director of the Center for Genomic Medicine at Dartmouth said, "This variant confers one the strongest associations found to date for cancer among those identified by genome-wide association studies, and identifies a subset of people who are particularly susceptible to harm associated with smoking."

The BRCA2 gene codes for a very large protein that functions primarily for coordinating activities of many different genes involved in DNA repair. Cells accumulate DNA damage as a result of environmental toxins such as those contained in tobacco smoke. Mutations in BRCA2 may affect the ability of cells to respond to DNA damage, increasing the chance that a cell will become a cancer.

Previous studies did not detect a connection between BRCA2 and lung cancer. All four GWA data set analyses in this study showed significant association of the BRCA2 gene (rs11571833) with non-small cell carcinoma, specifically squamous cell carcinoma. In addition, results validated previous studies connecting CHEK2 (rs17879961) with squamous cell carcinoma. The findings of the TP63 (rs13314271) variation in individuals in European ancestry provides robust evidence for its connection to adenocarcinoma.

"Our study showed that mutations to two genes, BRCA2 and CHEK2, have a very large effect on lung cancer risk in the context of smoking. Mutated BRCA2 in particular seems to increase risk by around 1.8 times," said study leader Richard Houlston, professor of Molecular and Population Genetics at The Institute of Cancer Research (ICR). "Smokers in general have nearly a 15 per cent chance of developing lung cancer, far higher than in non-smokers. Our results show that some smokers with BRCA2 mutations are at an enormous risk of lung cancer - somewhere in the region of 25 per cent over their lifetime. Lung cancer claims more than a million lives a year worldwide and is by far the biggest cancer killer in the UK. We know that the single biggest thing we can do to reduce death rates is to persuade people not to smoke, and our new findings make plain that this is even more critical in people with an underlying genetic risk."

The results of this study may influence how individuals are screened and treated for lung cancer. Those with genetic mutations who smoke may be candidates for lung cancer screening with low-dose CT scans. Since individuals with germline mutations of BRCA1 or BRCA2 respond to a specific chemotherapy called PARP inhibition, it is possible that individuals with this BRCA2 mutation and lung cancer may similarly respond more favorably to PARP inhibition than other lung cancer cases.